Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. It is estimated that there are 16,000,000 cases of typhoid fever every year, resulting in 600,000 deaths. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts, S. Typhi is an exclusive human pathogen. The molecular bases for the host adaptation and unique pathogenicity of these bacteria are poorly understood. However, it is believed that a combination of genome degradation and acquisition of new genetic information has conferred on S. Typhi its unique pathogenic properties. Work in our laboratory has recently focused on a pathogenicity islet that is unique to S. Typhi. We have discovered that this region of the chromosome encodes a Cytolethal Distending Toxin, and a Pertussis-like toxin. Remarkably, these toxins are only synthesized when S. Typhi reaches an intracellular location and are exported outside the cell by a unique transport mechanism to be subsequently delivered to target cells by novel paracrine and autocrine pathways. Furthermore, we have found that these toxins share a common unique secretion mechanism for export from the bacterial cytoplasm. In this research project, we intend to characterize this unique toxin delivery pathway and their unique secretion mechanism. We also would like to define their contribution to virulence in the context of S. Typhi pathogenesis and its interaction with host cells. These studies will provide insight into unique and important mechanisms of pathogenicity of S. Typhi, a surprisingly under study but very important human pathogen. PUBLIC HEALTH RELEVANCE: Salmonella enterica serovar Typhi (S. typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. It is estimated that there are 16,000,000 cases of typhoid fever every year, resulting in 600,000 deaths. Knowledge gained from this research should help develop novel therapeutic and prevention strategies.